Transdermal therapeutic systems are administration forms for percutaneous administration of pharmaceuticals. Among transdermal therapeutic systems, a distinction is made between reservoir systems and matrix systems. In the case of the reservoir systems, the pharmaceutical is present in the form of a liquid or semiliquid preparation in a flat reservoir whose wall comprises a membrane via which the pharmaceutical present in the reservoir can be delivered. Matrix systems are distinguished by the fact that the pharmaceutical is present in a polymer film. In their simplest embodiment, matrix systems consist of a pharmaceutical-impermeable backing layer, a pharmaceutical-containing matrix layer, which is usually self-adhesive, and a protective layer which is to be removed before use. However, there are also matrix systems of more complex construction, which may have two or more matrix layers of different compositions, an additional control membrane and/or else non-self-adhesive layers.
Pharmaceutical-containing polymer films are also in use, furthermore, for drugs intended for oral administration, as for example in the form of administration forms in sheet or film form. These drugs for oral administration may be based on a water-soluble polymer, and so the pharmaceutical is released rapidly when the administration form comes into contact with saliva. Water-insoluble or sparingly water-soluble polymers, preferably having mucoadhesive properties, are used for administration forms in sheet or film form with delayed release and/or for transmucosal administration of the pharmaceutical in the oral cavity.
Pharmaceutical-containing polymer films for oral or transdermal therapeutic systems are generally produced by applying a coating material, comprising the matrix-forming polymer or polymer mixture and the pharmaceutical, in a defined thickness to a substrate and then drying it. The coating of the substrate and the drying of the coating take place typically in one continuous operation. Drying in this context generally means the removal of the solvents.
The coating material is a solution or suspension comprising the matrix-forming polymer or the matrix-forming polymer mixture, at least one pharmaceutical, and optionally further excipients, examples being permeation enhancers, plasticizers, flavors, colorants, preservative, antioxidants or the like in a solvent. The solvent is preferably an organic solvent or a mixture of organic solvents.
The pharmaceutical itself may be, but need not be, completely dissolved in the solvent. In those cases where the pharmaceutical is to be fully dissolved in the solvent, there is a risk, even on slight exceedance of the saturation solubility for the pharmaceutical in the coating material, that crystallization nuclei will form in the coating material during coating of the substrate. Within the body of the coating, such crystallization nuclei are able to form as a result of a locally greater evaporation of the solvent or of one solvent component of the solvent mixture, area of a resultant local crystallization of the pharmaceutical.
The local crystallization of the pharmaceutical in the coating material is not a problem if the dried, solvent-free polymer film is subsaturated with pharmaceutical, since under these conditions the crystallization nuclei break up within a short time. The local crystallization of the pharmaceutical in the coating does constitute a problem, however, if she dried polymer film is also supersaturated with pharmaceutical or comprises pharmaceutical in an amorphous modification. Matrix systems supersaturated with pharmaceutical—and this includes systems which comprise the pharmaceutical in an amorphous form—have the advantage of particularly high thermodynamic activity and bioavailability of the pharmaceutical. This advantage, however, is contrasted by the disadvantage that the supersaturated matrix systems are metastable and the bioavailability or the pharmaceutical is severely adversely affected by its crystallization.
In order to prevent the formation of crystalline hydrates of active ingredients liquid at room temperature in a polymeric matrix layer, U.S. Pat. No. 4,832,953 proposed heating the pharmaceutical-containing polymer matrix. Described specifically is the formation of scopolamine hydrate crystals in nonaqueous, polymeric matrices, and an associated, significantly disadvantageous effect on the rate of release of scopolamine from the administration units, in which liquid scopolamine base is present in dispersion in a polyisobutylene/mineral oil matrix. To solve this problem, it is proposed that the ready-packed administration units be heated to 60° C. for a period of 24 hours. This heating of the administration units was sufficient to melt crystals of the scopolamine base hydrate present in the matrix, with a melting point of 59° C., and to prevent formation of crystals after the cooling of the administration units.
With administration units treated in this way, however, the occurrence of additional crystals was observed which had a relatively high melting temperature of 67-70° C. These additional crystals were not eliminated by the heating of the administration units to 60° C. for 24 hours. Nor was it possible to eliminate these additional crystals by raising the temperature to which the packaged administration units were heated. In order to solve this problem, U.S. Pat. No. 5,662,928 proposes heating the scopolamine-containing matrix layer—in addition to the heat treatment of the completed and ready-packaged administration units—to a temperature of between 67° C. and 90° C. for a period of 5 to 15 minutes, immediately prior to lamination with the release-controlling membrane. “Immediately”, according to U.S. Pat. No. 5,662,928, means that the lamination must take place within 24 hours, better still within 18 hours, after application of the scopolamine coating.
This known method for preventing crystallization of the pharmaceutical in the polymer matrix has the disadvantage that the matrix layer, after it has been coated, must be further-processed within a short time (24 hours) and can no longer be stored in the interim. This further heat treatment is an additional production step and renders the production method time-consuming and hence also costly.
The object on which the present invention was based was to find a simple and cost-effective way to prevent the crystallization of pharmaceutical in a polymer matrix supersaturated with this pharmaceutical.